Identification of the first specific inhibitor of p90 ribosomal S6 kinase (RSK) reveals an unexpected role for RSK in cancer cell proliferation.

Smith JA, Poteet-Smith CE, Xu Y, Errington TM, Hecht SM, Lannigan DA
Cancer Res. 2005 65 (3): 1027-34

PMID: 15705904

p90 ribosomal S6 kinase (RSK) is an important downstream effector of mitogen-activated protein kinase, but its biological functions are not well understood. We have now identified the first small-molecule, RSK-specific inhibitor, which we isolated from the tropical plant Forsteronia refracta. We have named this novel inhibitor SL0101. SL0101 shows remarkable specificity for RSK. The major determinant of SL0101-binding specificity is the unique ATP-interacting sequence in the amino-terminal kinase domain of RSK. SL0101 inhibits proliferation of the human breast cancer cell line MCF-7, producing a cell cycle block in G(1) phase with an efficacy paralleling its ability to inhibit RSK in intact cells. RNA interference of RSK expression confirmed that RSK regulates MCF-7 proliferation. Interestingly, SL0101 does not alter proliferation of a normal human breast cell line MCF-10A, although SL0101 inhibits RSK in these cells. We show that RSK is overexpressed in approximately 50% of human breast cancer tissue samples, suggesting that regulation of RSK has been compromised. Thus, we show that RSK has an unexpected role in proliferation of transformed cells and may be a useful new target for chemotherapeutic agents. SL0101 will provide a powerful new tool to dissect the molecular functions of RSK in cancer cells.

MeSH Terms (15)

Amino Acid Sequence Benzopyrans Breast Neoplasms Cell Growth Processes Cell Line, Tumor Enzyme-Linked Immunosorbent Assay Humans Molecular Sequence Data Monosaccharides Phosphorylation Plant Extracts Protein Kinase Inhibitors Protein Structure, Tertiary Ribosomal Protein S6 Kinases, 90-kDa Substrate Specificity

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